Alzheimer disease (AD) is the most common form of age-related dementia, in part characterized by senile plaques composed of beta-amyloid protein in cognitive and affective brain regions. Much research in the area of AD neuropathogenesis has focused on the production of beta-amyloid from its precursor protein APR (beta-amyloid precursor protein). However, limited knowledge exists on the potential ligands of APP, which may mediate APP signal transduction and subsequent beta-amyloid production. Recently, in collaboration with Dr. P. Mehlen (Univ. of Lyon), we have identified a novel neurotrophic ligand for APP, netrin-1, and posited a model of APP signal transduction that results in a significant decrease in net beta- amyloid levels. In order to establish a framework for the therapeutic manipulation of AD, this proposal seeks to further investigate the potential role of netrin-1 as an APP ligand in amelioration of certain elements of the AD phenotype. With this goal in mind, the specific aims present a plan to 1) validate netrin-1's ability to modulate beta-amyloid production and other AD-like traits (i.e., dentate gyral atrophy, synapse loss, and working memory in a Y-maze) in vivo by establishing an AD transgenic mouse model that inducibly expresses netrin-1; and 2) using deletion mutant designs, I plan to identify, and then purify the minimum APP-binding and biologically active domain of netrin-1 that suppresses net beta-amyloid production like full- length netrin-1. We hypothesize that netrin-1 expression, through binding with APP, will decrease beta- amyloid levels in brain, with a related amelioration of AD-like features. Furthermore, if a netrin-1-derived fragment is discovered that is mechanistically similar to netrin-1, then it may be feasible as a therapeutic compound in the treatment of AD. [unreadable] [unreadable]